Systemic anti-inflammatory treatment of atopic dermatitis during conception, pregnancy and breastfeeding: Interdisciplinary expert consensus in Northern Europe.

Treating atopic dermatitis (AD) in pregnant or breastfeeding women, and in women and men with AD aspiring to be parents is difficult and characterized by uncertainty, as evidence to inform decision-making on systemic anti-inflammatory treatment is limited. This project mapped consensus across dermatologists, obstetricians and patients in Northwestern Europe to build practical advice for managing AD with systemic anti-inflammatory treatment in men and women of reproductive age. Twenty-one individuals (sixteen dermatologists, two obstetricians and three patients) participated in a two-round Delphi process. Full consensus was reached on 32 statements, partial consensus on four statements and no consensus on four statements. Cyclosporine A was the first-choice long-term systemic AD treatment for women preconception, during pregnancy and when breastfeeding, with short-course prednisolone for flare management. No consensus was reached on second-choice systemics preconception or during pregnancy, although during breastfeeding dupilumab and azathioprine were deemed suitable. It may be appropriate to discuss continuing an existing systemic AD medication with a woman if it provides good disease control and its benefits in pregnancy outweigh its risks. Janus kinase (JAK) inhibitors, methotrexate and mycophenolate mofetil should be avoided by women during preconception, pregnancy and breastfeeding, with medication-specific washout periods advised. For men preconception: cyclosporine A, azathioprine, dupilumab and corticosteroids are appropriate; a 3-month washout prior to conception is desirable for methotrexate and mycophenolate mofetil; there was no consensus on JAK inhibitors. Patient and clinician education on appropriate (and inappropriate) AD treatments for use in pregnancy is vital. A shared-care framework for interdisciplinary management of AD patients is advocated and outlined. This consensus provides interdisciplinary clinical guidance to clinicians who care for patients with AD before, during and after pregnancy. While systemic AD medications are used uncommonly in this patient group, considerations in this article may help patients with severe refractory AD.

Effect of upadacitinib on atopic hand eczema in patients with moderate-to-severe atopic dermatitis: Results from two randomized phase 3 trials.

BACKGROUND: Approximately 60% of patients with atopic dermatitis have involvement of the hands adding to the burden of disease. OBJECTIVE: This analysis aims to evaluate the effect of upadacitinib monotherapy on atopic hand eczema in patients with moderate-to-severe AD over 16 weeks in the Measure Up 1 and 2 studies. METHODS: Data from patients (ages 12-75) randomized 1:1:1 to receive upadacitinib 15 mg, 30 mg, or placebo once daily in the Measure Up 1 and 2 studies were analysed for impact on atopic hand eczema assessed using the Hand Eczema Severity Index (HECSI). The percent change from baseline in HECSI score was a prespecified additional endpoint at all visits. The proportion of patients with at least a 75% improvement in HECSI score (HECSI 75) was evaluated post hoc. RESULTS: Patients treated with upadacitinib 15 mg or 30 mg experienced greater improvement in HECSI score compared with placebo as early as Week 1, which was maintained through Week 16. At Week 16, the mean change from baseline in HECSI score for patients receiving upadacitinib 15 mg, 30 mg, and placebo was -68%, -74%, and -15% in Measure Up 1 and -68%, -74% and +21% (positive change indicates worsening for placebo) in Measure Up 2, respectively. A greater proportion of upadacitinib-treated patients achieved HECSI 75 compared with placebo at all timepoints beginning at Week 1 through Week 16. CONCLUSIONS: Upadacitinib 15 mg and 30 mg monotherapy provided rapid and sustained improvement in atopic hand eczema compared with placebo through Week 16 in patients with moderate-to-severe AD. At Week 16, the observed mean improvements in HECSI score in upadacitinib-treated patients were clinically meaningful based on previous interpretability studies. These results suggest that upadacitinib may be an effective treatment option for atopic hand eczema in patients with moderate-to-severe AD.

Systemic treatment of children and adolescents with atopic dermatitis aged ≥2 years: a Delphi consensus project mapping expert opinion in Northern Europe.

BACKGROUND: Paediatric atopic dermatitis (AD) can be burdensome, affecting mental health and impairing quality of life for children and caregivers. Comprehensive guidelines exist for managing paediatric AD, but practical guidance on using systemic therapy is limited, particularly for new therapies including biologics and Janus kinase (JAK) inhibitors, recently approved for various ages in this indication. OBJECTIVES: This expert consensus aimed to provide practical recommendations within this advancing field to enhance clinical decision-making on the use of these and other systemics for children and adolescents aged ≥2 years with moderate-to-severe AD. METHODS: Nineteen physicians from Northern Europe were selected for their expertise in managing childhood AD. Using a two-round Delphi process, they reached full or partial consensus on 37 statements. RESULTS: Systemic therapy is recommended for children aged ≥2 years with a clear clinical diagnosis of severe AD and persistent disease uncontrolled after optimizing non-systemic therapy. Systemic therapy should achieve long-term disease control and reduce short-term interventions. Recommended are cyclosporine A for short-term use (all ages) and dupilumab or methotrexate for long-term use (ages ≥6 years). Consensus was not reached on the best long-term systemics for children aged 2-6 years, although new systemic therapies will likely become favourable: New biologics and JAK inhibitors will soon be approved for this age group, and more trial and real-world data will become available. CONCLUSIONS: This article makes practical recommendations on the use of systemic AD treatments for children and adolescents, to supplement international and regional guidelines. It considers the systemic medication that was available for children and adolescents with moderate-to-severe AD at the time this consensus project was done: azathioprine, cyclosporine A, dupilumab, methotrexate, mycophenolate mofetil and oral glucocorticosteroids. We focus on the geographically similar Northern European countries, whose healthcare systems, local preferences for AD management and reimbursement structures nonetheless differ significantly.

Validation of questionnaire algorithm based on repeated open application testing with the constituents of fragrance mix II: the EDEN Fragrance Study.

BACKGROUND: In a European study on contact allergy in the general population, it has been hypothesized that the combination of contact allergy to a fragrance together with a history indicating dermatitis at exposure and thereafter subsequent avoidance of scented products implied a diagnosis of allergic contact dermatitis. OBJECTIVES: The primary aim of this study was to validate this hypothesis/algorithm. The secondary aim was to investigate whether there was any association between the outcome of the recent repeated open application test (ROAT) and the patch test reactivity. METHODS: One hundred nine subjects with and without contact allergy to fragrance mix II (FM II) were recruited. Volunteers from six European dermatology clinics participated in the study including a patch test and a ROAT. RESULTS: Twenty-four positive ROAT reactions were noted in total including 20 of those 32 with contact allergy to FM II. None of the volunteers reacted to the vehicle (P < 0.001). More individuals with a positive algorithm had positive ROATs when compared with those with a negative algorithm. However, the difference was not statistically significant (P = 0.12). The lower the patch test concentration eliciting a positive test reaction, the more likely was a positive ROAT and the more likely that the positive ROAT appeared early during the investigative period. CONCLUSIONS: The algorithm used in this study was not validated but it was indicated in this ROAT setup. The stronger the patch test reactivity the more likely was a positive ROAT and the more likely it was that the positive ROAT appeared early during the application period.

Protocol for the development of a core domain set for hand eczema trials.

BACKGROUND: Clinical hand eczema trials measure a variety of outcome domains to determine the success of interventions. This considerably limits the comparability and overall confidence in the study results, and thereby the strength of recommendations for clinical practice. OBJECTIVES: The Hand Eczema Core Outcome Set (HECOS) initiative aims to develop a core outcome set (COS) for the standardized evaluation of interventions in future hand eczema trials and reviews. This COS will define the minimum that should be measured and reported in controlled and randomized-controlled trials of therapeutic hand eczema interventions. The objective of this protocol is to specify the methods to develop a core domain set. METHODS: In Phase 1, a list of candidate domains will be derived from a systematic literature review concerning previously measured outcomes in hand eczema trials, from qualitative patient interviews and from expert interviews. In Phase 2, a consensus study about core domains will be conducted by an online 3-round Delphi survey and a face-to-face meeting, applying predefined consensus criteria. HECOS involves hand eczema and methods experts as well as patients and further stakeholders with an interest in the initiative. OUTLOOK: When a set of core domains has been defined, HECOS is going to identify appropriate outcome measurement instruments in a development process that will be detailed in another protocol. The COS will considerably enhance the methodological quality, comparability and usefulness of hand eczema trials for clinical decision-making and the development of new therapeutic options for hand eczema, and also reduce the effort of planning, conducting, and reporting individual hand eczema studies, reviews and meta-analyses.

Validation of the Dutch Quality of Life in Hand Eczema Questionnaire (QOLHEQ).

BACKGROUND: Measurement instruments should be validated for use in the population for which they are intended. The Quality of Life in Hand Eczema Questionnaire (QOLHEQ) has been developed to measure impairment of health-related quality of life in patients with hand eczema. OBJECTIVES: To assess validity, reproducibility, responsiveness and interpretability of the Dutch version of the QOLHEQ. METHODS: This was a prospective validation study in adult patients with hand eczema. At three time points (T0 , baseline; T1 , after 1-3 days; T2 , after 4-12 weeks), data from the QOLHEQ and multiple reference instruments were collected. Scale structure was assessed using item response theory analysis and structural equation modelling (SEM). Single-score validity and responsiveness were tested with hypotheses on correlations with reference instruments. Concerning reproducibility, intraclass correlation coefficients (ICCagreement ) and standard error of agreement (SEMagreement ) were checked. Regarding interpretability, bands for severity of quality-of-life impairment were proposed. Also, smallest detectable change (SDC) and minimally important change (MIC) were determined. RESULTS: At T0 , 300 individuals participated in the study (54% were male, mean age 45 years). Rescoring of the scale structure fitted the Rasch model and the SEM. The ICCagreement was 0·91 (95% confidence interval 0·85-0·94) and the SEMagreement was 5·2 points. Of the a priori formulated hypotheses, 80% (single-score validity) and 64% (change scores for responsiveness) were confirmed. The SDC was 14·4 points and the MIC was 11·5 points. CONCLUSIONS: The Dutch version of the QOLHEQ has a good structural validity and reproducibility and has a high single-score validity and moderate responsiveness. An improvement of ≥ 15 points should be regarded as a real, important change within the Dutch population. What's already known about this topic? The Quality of Life in Hand Eczema Questionnaire (QOLHEQ) measures impairment of health-related quality of life (HRQoL) in patients with hand eczema. The QOLHEQ was validated in Germany and Japan, but the validity and interpretability of the Dutch version are unknown. What does this study add? This study shows that the Dutch QOLHEQ is a valid instrument to measure HRQoL impairment in Dutch patients with hand eczema, demonstrating good reliability and moderate responsiveness. Methods of item response theory are applied to assess and refine the scoring structure. Severity gradings to interpret single and change scores, specifically in Dutch patients, are proposed. What are the clinical implications of this work? The Dutch QOLHEQ can now be used to measure HRQoL impairment in Dutch patients with hand eczema.

Validation of a questionnaire algorithm based on repeated open application testing with the constituents of fragrance mix I.

BACKGROUND: In a European study on contact allergy in the general population, it was hypothesized that the combination of contact allergy to a fragrance together with a history indicating dermatitis at exposure, and thereafter subsequent avoidance of scented products, implied a diagnosis of allergic contact dermatitis. OBJECTIVES: The primary aim of this study was to validate this hypothesis and algorithm. The secondary aim was to investigate whether there was any association between the outcome of the repeated open application test (ROAT) and the patch test reactivity. METHODS: In total, 109 patients with and without contact allergy to fragrance mix (FM) I were recruited. Volunteers from six European dermatology clinics participated in the study including a patch test and a ROAT. RESULTS: Positive ROAT reactions were noted in 26 of the 44 volunteers with contact allergy to FM I. None of the volunteers reacted to the vehicle (P < 0·001). More individuals with a positive algorithm had positive ROATs than those with a negative algorithm. However, the difference was not statistically significant. The lower the patch test concentration eliciting a positive test reaction, the more likely a positive ROAT and the more likely that the positive ROAT appeared early during the investigative period. CONCLUSIONS: The algorithm used in this study was not substantiated in this ROAT set-up. The stronger the patch test reactivity the more likely was a positive ROAT and the more likely it was that the positive ROAT appeared early during the application period. What's already known about this topic? To the best of our knowledge, a scientifically designed and conducted repeated open application test (ROAT) has never been performed before to validate a diagnosis of allergic contact dermatitis partly based on a questionnaire. What does this study add? This is the largest controlled, randomized and blinded ROAT performed to date. Higher patch test reactivity to fragrance mix I indicated a greater likelihood of a positive ROAT. What are the clinical implications of this work? Further refinement of the questions is required in order to diagnose allergic contact dermatitis from fragrances based on a questionnaire.

Responsiveness and interpretability of the Hand Eczema Severity Index.

BACKGROUND: The Hand Eczema Severity Index (HECSI) is used to measure the severity of hand eczema. It is unclear what HECSI scores mean and what is the minimally important change (MIC). Furthermore, its responsiveness has not been studied. OBJECTIVES: To study the responsiveness and interpretability of the HECSI. METHODS: This was a prospective study covering two time points: baseline and after 4-12 weeks. Responsiveness was assessed using a criterion approach, with at least one-step improvement on the 'Photographic guide for severity of hand eczema' as the anchor for important improvement. Interpretability of single scores was determined by defining severity bands based on agreement with the anchor. For change scores, the smallest detectable change (SDC) was calculated in patients indicating no change and the MIC was obtained in patients indicating that they had changed using three methods: mean cutoff, receiver operating characteristic (ROC) curve and 95% limit. RESULTS: In total, 294 patients participated (160 male, mean age 44·9 years). HECSI scores improved or deteriorated in parallel with the anchor. The area under the ROC curve was 0·86 (95% confidence interval 0·81-0·91). The final severity band for single scores had a κ-coefficient of agreement of 0·694: clear, 0; almost clear, 1-16; moderate, 17-37; severe, 38-116; very severe, ≥ 117. The SDC in 93 unchanged patients was 40·3 points. The obtained MIC values were all smaller than the SDC. CONCLUSIONS: The HECSI has good responsiveness. This study gives meaning to HECSI scores, which can be applied to clinical decision making and the design of clinical trials. We recommend that an improvement of 41 points on the HECSI is regarded as the minimally measurable true change. What's already known about this topic? The Hand Eczema Severity Index (HECSI) is one of the most widely used measurement instruments to measure the severity of hand eczema. The HECSI has good reliability, but its responsiveness and interpretability have not been studied. What does this study add? This study shows good responsiveness of the HECSI. A severity grading for single scores is proposed. The smallest detectable change and minimally important change for improvement are determined. What are the clinical implications of this work? The obtained values help to interpret HECSI scores in daily practice and clinical studies, and may facilitate researchers in the calculation of sample sizes for clinical trials.

Hand eczema among Dutch beekeepers - a cross-sectional study.

BACKGROUND AND OBJECTIVES: Studies of beekeepers have mostly focused on contact allergy to propolis. The overall prevalence of hand eczema (HE) in beekeepers has not been studied. Our objectives were to gain insight into the prevalence of HE in the Dutch beekeeper population; to define the impact of beekeeping activities on HE and vice versa; and to determine associated factors. PATIENTS AND METHODS: We used a cross-sectional online survey. Dutch beekeepers answered questions on beekeeping activities, the prevalence and characteristics of HE, including severity, and the impact of the disease on beekeeping. RESULTS: We analyzed 833 surveys (12 % of Dutch beekeepers). The one-year prevalence of HE was 13.2 %, and the lifetime prevalence was 20.5 %. In 28 patch-tested beekeepers with hand eczema, eight (28.6 %) were allergic to propolis. Atopic dermatitis was the only variable associated with HE: the odds ratio was 4.53 (95 % confidence interval 2.78-7.38). One in three beekeepers reported that HE was caused or worsened by beekeeping, although only 3.8 % reported working less at beekeeping because of HE, and the impact of HE on beekeeping activities (as perceived by beekeepers) is low. CONCLUSIONS: In this sample of Dutch beekeepers, hand eczema was more prevalent than in the general population, but seems to have had little impact on the beekeeping activities of the majority of beekeepers.

Defining and measuring 'eczema control': an international qualitative study to explore the views of those living with and treating atopic eczema.

BACKGROUND: Atopic eczema (also known as eczema) is a chronic, inflammatory skin condition that often afflicts patients' health and well-being. The Harmonising Outcome Measures for Eczema (HOME) initiative recommends that 'long-term control of eczema' is measured in all clinical trials 3 months or longer in duration. However, little has been published on what eczema control means to those living with or treating atopic eczema. OBJECTIVES: To (i) develop understanding of what eczema control means to patients, carers and clinicians and (ii) explore the feasibility and acceptability of different ways of measuring eczema control in the long term. METHODS: Online focus groups explored patients/carers experiences in the UK, the United States, the Netherlands, France, Sweden and Japan, and an international online survey gathered views of clinicians. The framework method was used to analyse the focus groups, and thematic analysis was used to analyse survey data. All findings were integrated into a theoretical framework to create overarching themes that cut across these diverse groups. RESULTS: Eight focus groups with patients (16 years+) and eight groups with carers of children took place (N = 97). Sixty-two people took part in the survey. Eczema control was described as a multifaceted construct involving changes in disease activity, the treatment and management of the condition and psychological, social and physical functioning. Patient/carer measurement allows personal accounts and frequent measurement, whilst clinician measurement was deemed less subjective. The burden on patients/carers and issues for analysing and interpreting data should be considered. CONCLUSIONS: This study formed the basis of judging the content validity and feasibility of measurement instruments/methods to assess control of eczema in clinical trials. This online approach to an international qualitative study is an example of how core outcome set developers with limited resources can engage with multiple stakeholder groups on an international basis to inform consensus meeting discussions.

Is there an increased risk of cervical neoplasia in atopic dermatitis patients treated with oral immunosuppressive drugs?

BACKGROUND: Oral immunosuppressive drugs are frequently prescribed in young women with atopic dermatitis (AD). Immunocompromised patients may have a higher risk of developing high-risk HPV infections, cervical intra-epithelial neoplasia (CIN) and cervical carcinoma. Most literature on patients using oral immunosuppressive drugs is available in organ transplant patients. Literature on the risk of developing cervical carcinoma in AD patients treated with oral immunosuppressive drugs is lacking. At this moment, there is no clear guideline/consensus on this topic, but in daily practice, questions arise concerning whether this risk is increased and whether more intensive screening in women using immunosuppressive drugs should take place. OBJECTIVE: To investigate the occurrence of cervical carcinoma in women with AD treated with oral immunosuppressive drugs. METHODS: In this retrospective cohort study in two university medical centres in the Netherlands, all female adult AD patients receiving oral immunosuppressive drugs (cyclosporine A, azathioprine, methotrexate, mycophenolate mofetil, enteric-coated mycophenolate sodium and extended release tacrolimus) for more than 2 months between 1989 and 1 January 2014 were included. Patient files in the national histopathology register were screened for PAP3a, CIN I, CIN II, CIN III and cervical carcinoma. RESULTS: A total of 257 female AD patients with one or more treatment episodes from 1989 until 1 January 2014 were identified and included in this study. In 189 patients (73.5%), results of cervical examination were reported in the national histopathology database. Median total duration of treatment in these 189 women was 407.0 days (IQR 243.0-940.0). No cervical carcinoma during or following immunosuppressive therapy was found in our patient group. CONCLUSIONS: No intensified screening programme for cervical neoplasia seems necessary for women with AD using oral immunosuppressive drugs.

Prevalence of skin disease in a population-based sample of adults from five European countries.

BACKGROUND: There is a lack of prevalence data on skin diseases in the general adult population; most studies have been carried out in small, national or consecutive clinical samples. OBJECTIVES: To determine the prevalence of common skin disease in the general European population and to assess differences in the characteristics of treatment between countries. METHODS: A random sample consisting of 12 377 participants aged 18-74 years was drawn from the general population of five European countries (Germany, Italy, the Netherlands, Portugal and Sweden). This was a cross-sectional study and all participants were interviewed using a standardized questionnaire that assessed the occurrence of 10 common skin diseases during lifetime, past year and past month. If a skin disease was reported, we additionally assessed who performed the diagnosis and treatment, and whether drugs had been prescribed. RESULTS: The most common skin disease was warts (41·3%), followed by acne (19·2%) and contact dermatitis (15·0%). In general, women were more often affected by skin diseases compared with men; only skin cancer had a slightly higher prevalence in men. The prevalence of skin diseases in northern countries (Germany, the Netherlands and Sweden) was generally higher than in the southern countries (Italy and Portugal). In the Netherlands the treatment of skin diseases was less often performed by a dermatologist compared with the other countries. CONCLUSIONS: The prevalence estimates reported in this study are derived from a representative sample of the general population. Data assessment was performed comprehensively across countries, thus country-specific prevalence estimates are comparable.

European Surveillance System on Contact Allergies (ESSCA): results with the European baseline series, 2013/14.

BACKGROUND: Contact allergy is a common condition and can severely interfere with daily life or professional activities. Due to changes in exposures, such as introduction of new substances, new products or formulations and regulatory intervention, the spectrum of contact sensitization changes. OBJECTIVE: To evaluate the current spectrum of contact allergy to allergens present in the European baseline series (EBS) across Europe. METHODS: Retrospective analysis of data collected by the European Surveillance System on Contact Allergies (ESSCA, www.essca-dc.org) in consecutively patch-tested patients, 2013/14, in 46 departments in 12 European countries. RESULTS: Altogether, 31 689 patients were included in the analysis. Compared to a similar analysis in 2004, the prevalence of contact allergy to methylisothiazolinone went up to around 20% in several departments. In comparison, contact allergy to the metals nickel, cobalt and chromium remained largely stable, at 18.1%, 5.9% and 3.2%, respectively, similar to mostly unchanged prevalence with fragrance mix I, II and Myroxylon pereirae (balsam of Peru) at 7.3%, 3.8% and 5.3%, respectively. In the subgroup of departments diagnosing (mainly) patients with occupational contact dermatitis, the prevalence of work-related contact allergies such as epoxy resin or rubber additives was found to be increased, compared to general dermatology departments. CONCLUSION: Continuous surveillance of contact allergy based on network data offers the identification of time trends or persisting problems, and thus enables focussing in-depth research (subgroup analyses, exposure analysis) on areas where it is needed.